



-,drolysis, etc. .quire several steps to convert the originally formedsub- United States Patent ""ce METHOD OF PREPARING VITAMIN Be John S.Webb, Warren Township, Somerset County, N. .L, assignor to AmericanCyanamid Company, New York, N. Y., a corporation of Maine 7 No Drawing.Application July 30, 1953, Serial No. 371,430

6 Claims. (Cl. 260-2975) This invention relates to the preparation ofvitamin Be. More particularly, it relates to the preparation of vitaminB6 from substituted furans by a one-step process.

In the past vitamin B6 (2-methyl-3-hydroxy-4,5-pyridine dimethanol) hasbeen synthesized by the preparation of variously substituted pyridinecompounds and the sub- .sequent conversion of said substituent groups tothose present in the vitamin by such processes as reduction,

nitration, chlorination, diazotization, aminolysis, hy-

Consequently all of these processes re- ;stituted pyridine to vitaminB5.

I have now found that vitamin B6 can be prepared -from2-aceto-3,4-furandimethanol, its O-acyl derivatives .or ethers in asimplified process by heating said compounds with an ammonium salt inthe presence of water. In the case of the ethers a subsequent ethercleavage step is required to give vitamin B6. The reaction which takesplace can be illustrated by the following formula:

CHzOH /CHnO-R ammonium Salts HOHzC OH water 0: CH; CHzO-R N pounds andare described and claimed in my copending application, Serial Number371,429, filed July 30, 1953. These intermediates or starting materialscan be compounds such as 2-aceto-3,4-bis(acetoxymethyl)furan; 2- aceto3,4 bis (propionoxymethyl)furan; 2-aceto-3,4-bis-(butyryloxymethyDfuran; 2 aceto 3,4 bis(formoxy methyl)furan;2-aceto-3,4-bis(benzoxymethyl)furan; 2- aceto 3,4bis(furoxymethyl)furan; 2 aceto 3,4 bis- (phenylacetoxymethyl)furan; 2aceto-3,4-bis (methoxymethyl)furan; 2 aceto 3,4-bis(ethoxymethyl)furan;2- aceto 3,4 bis(propoxymethyl)furan; 2 aceto 3,4-bis-(phenoxymethyl)furan; 2 aceto 3,4 bis(benzyloxy)- methylfuran; etc. Alsomixed O-acyl derivatives and ethers of 2-aceto-3,4-furandimethanol canbe used in the process of the present invention. While 2-aceto-3,4-furandimethanol itself can be used, it is generally desirable to use adiacyl derivative thereof since the intermediate is preferably preparedin this form. It is believed that formation of the pyridine ring takesplace followed by hydrolysis of the acyloxy linkage. However, thehydrolysis may occur first followed by formation of the 2,732,379Patented Jan. 24, 1956 pyridine ring, and applicant does not wish to bebound by any particular order of reaction.

The ammonium salts found most useful in the present process are those ofthe inorganic acids such as ammonium chloride; ammonium sulfate;ammonium phosphate; ammonium nitrate; and the like. However, otherammonium salts can be used such as the acetate. Best results have beenobtained by the use of an ammonium salt along with ammonium hydroxide.However, ammonium hydroxide is not essential in the reaction as shown inthe examples hereinafter.

The process of the present invention is preferably carried out at therefluxing temperature of the reaction mixture. The process, however, canbe carried out at a temperature of from 50 C. to 175 C. The timenecessary to complete the reaction is dependent upon the temperature andintermediates used and will vary from one to thirty-six hours.

The following examples describe the process of the present invention ingreater particularity and are intended to be by way of illustration andnot limitation.

Example 1 A solution of 37 g. of dimethyl 3,4-furan dicarboxylate(prepared according to the procedure of Alder and Rickert, Ber. 70,1354) dissolved in 400 ml. of absolute ether is added dropwise duringstirring to 15.2 g. of lithium aluminum hydride in 800 ml. of absoluteether over a period of about one hour. The resulting mixture is stirredtwo hours at room temperature and then 52 ml. of ethyl acetate is addeddropwise during rapid stirring. Following this, ml. of water is addeddropwise also during rapid stirring. The ether layer is then decantedfrom the resulting mass of alumina gel and the latter extracted bystirring several minutes each with two 400 ml. portions of ether. Theoriginal other layer and the two extracts are then combined and driedover anhydrous sodium sulfate. Filtration of the drying agent andremoval of the ether by distillation on the steam bath leaves a residueof a pale yellow somewhat viscous syrup. This material is vacuumdistilled at a pressure of 1 mm. and the fraction boiling at 115120 C.collected to give 18.5 g. of 3,4-furandimethanol, a colorless, watersoluble syrup with an index of refraction n =1.5073.

3,4-furandimethanol (16 g.), acetic anhydride (50 ml.) and pyridine (0.2ml.) are heated together on a steam bath for two hours. The resultingmixture is then vacuum distilled at 20 mm. from a steam bath to removethe excess acetic anhydride and the acetic acid formed in the reaction.The residue is then further distilled at a pressure of 0.7 to 0.9 mm.and the material boiling at 104106 C. is collected to yield 25.7 g. of3,4bis- (acetoxymethyl)furan in the form of a colorless oil which has arefractive index of 1.4668 at 26. On cooling to a low temperature theoil crystallizes to colorless irregular plates which melt at 30-30.5 C.

3,4-bis(acetoxymethyl)furan-, 2.1 g., is dissolved in acetic anhydride,1.0 ml. To this is added a mixture of 85% phosphoric acid, 0.2 ml., inacetic anhydride, 1.0 ml. The mixture is warmed to 50 C. for a fewminutes then sealed from the air and set aside at room temperatureovernight. The reaction mixture is then diluted with water, 20 ml., andagitated until the odor of acetic anhydride disappears. The resultingoil is extracted from the aqueous solution with several portions ofether which are combined, washed with a saturated solution of sodiumbicarbonate and finally dried with anhydrous sodium sulfate. Afterfiltration from the drying agents the ether is distilled on the steambath leaving a residue of yellowish oil. This is vacuum distilled at apressure of 1 mm. and the colorless oil which boils in the range of 150C. is collected. Most of this oil boils in the range of 145l48 C. at 1mm. pressure. On cooling and scratching the oil crystallizes. Theproduct is recrystallized from a mixture of ethyl ether-petroleum etherto give pure 2-aceto-3,4-bis(acetoxymethyl)furan in the form of large,irregular white crystals having a melting point of Sl52 C. It gives apositive iodoform test and forms a p-nitrophenylhydrazone derivativewhich has a melting point of 208"2l0 C.

2-aceto3,4-bis(acetoxymethyl)furan, l g., and ammonium chloride, 20 g.,are refluxed together in 30 ml. of water for 30 hours. A clear solutionis obtained in 5 to 22 hours and the final reaction mixture is nearlycolorless. This is diluted and filtered to yield a solution containingpyridoxine as demonstrated by both chemical and microbiological assay.

Example 2 1 g. of 2-aceto-3,4-bis(acetoxymethyl)furan is heated forthree hours at 100 C. in a solution prepared from a 4 g. of ammoniumchloride, and 4 ml. of concentrated ammonium hydroxide plus water tomake 25 milliliters. A clear, nearly colorless solution is obtainedwhich contains vitamin Be as indicated by colorimetric and bioassay.

Example 3 2 g. of 2-aceto-3,4-bis(acetoxymethyl)furan, 5 g. of ammoniumsulfate and 50 ml. of Water are heated together in a sealed tube at 160for two hours. The resulting light brown solution is then clarified toremove the small amount of insoluble material present to yield asolution containing vitamin B6.

Example 4 2-aceto-3,4-furandimethanol, l g., and ammonium chloride, 20g., are refluxed together in 30 ml. of water for six hours. At the endof this time a sample of the clear, nearly colorless reaction mixture isdiluted to double volume to yield a solution containing pyridoxine.

I claim I. A method of preparing vitamin B6 which comprises heating a.compound having the formula:

/CH20R J:

in which R is a member of the group consisting of hydrogen and a loweralkanoic acyl radical, with an ammonium salt of a strong inorganic acidin the presence of water and recovering said product.

2. A method of preparing vitamin B6 which comprises heating a loweralkanoic acyl derivative of 2-aceto-3,4- furandimethanol with anammonium salt of a strong inorganic acid in the presence of water andrecovering said product.

3. A method of preparing vitamin B6 which comprises heating2-aceto-3,4-furandimethanol with an ammonium salt of a strong inorganicacid in the presence of water and recovering said product.

4. A method of preparing vitamin B which comprises heating2-aceto-3,4-bis(acetoxymethyl)furan with ammonium chloride in thepresence of water and recovering said product.

5. A method of preparing vitamin B6 which comprises heating2-aceto-3,4-bis (acetoxymethyl)furan with ammonium chloride in thepresence of aqueous ammonium hydroxide and recovering said product.

6. A method of preparing vitamin B6 which comprises heating2-aceto-3,4-bis(acetoxymethyl)furan with ammonium sulfate in thepresence of water and recovering said product.

No references cited.

1. A METHOD OF PREPARING VITAMIN B6 WHICH COMPRISES HEATING A COMPOUNDHAVING THE FORMULA: